This is a revised (A1) competitive renewal application for an R01 initially focused on the role of a novel homeodomain protein called Hop that we discovered in the embryonic heart. We have found that Hop loss of function results in a developmental cardiac defect and that over-expression results in cardiac hypertrophy. Hop can function at the molecular level as a transcriptional co-repressor by recruiting class I HDACs. This finding led us to test the effects of HDAC inhibitors and we have found that these agents can block cardiac hypertrophy induced by Hop over-expression and also hypertrophy resulting from other stresses including beta-adrenergic agonists and stretch. Therefore, we have sought the specific class I HDAC(s) that account for these effects, and we have identified high levels of HDAC2 in the developing and adult heart. HDAC2 loss of function results in mice that are resistant to Hop- induced cardiac hypertrophy and to hypertrophy induced by beta-adrenergic agonists. We have shown that resistance to hypertrophy in these models is caused by constitutive activation of GSK3-beta, since antagonists of GSK3-beta restore the ability to hypertrophy on HDAC2 null animals. Our data indicates that HDAC2 affects the AKT-GSK3-beta pathway by directly repressing a novel inositol polyphosphate phosphatase called INPP5F, which functions to degrade PIP3 and thus affects the AKT cascade. These findings have direct clinical and translational implications since phosphatases are excellent drugable targets for the treatment of cardiovascular disease and because HDAC inhibitors are already in clinical trials for the treatment of cancer and could be readily adapted for use in the cardiac arena. Therefore, we will pursue these observations by: 1) Developing a floxed allele of HDAC2 in order to perform tissue and temporal specific deletion and to determine the effects of HDAC2 loss of function on regression of pre-established hypertrophy; 2) Elucidation of the genetic and biochemical interaction between Hop and HDAC2, and; 3) Examination of the function of INPP5F through gain and loss of function approaches in cells and in mice. These experiments offer strong prospects for developing new therapeutic avenues and paradigms for the treatment of cardiac hypertrophy and heart failure, with implications for the more general fields of cellular and organ growth regulation. PUBLIC HEALTH RELEVANCE: This project focuses on the causes of congestive heart failure, and on finding new therapeutic targets. Heart failure is a leading cause of death and disability in the United States, and the incidence is rising. We have found that HDAC inhibitors, which are drugs currently in clinical trials for cancer therapy, have beneficial effects in terms of heart failure prevention in animal models. This project explores the possibility that an enzyme called HDAC2, expressed in the heart, is the molecular target for HDAC inhibitors, and that it functions by regulating a novel phosphatase in the heart called INPP5F. We hope to determine if HDAC2 and INPP5F represent new targets for the development of specific therapies for heart disease.